Cyclodextrins are cyclic oligosaccharides which possess a toroidal structure and harbor hydrophobic/lipophilic central cavities and hydrophilic outer surfaces. A number of different cyclodextrin structures exist in nature, the most prominent being α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, which consist of 6, 7 and 8 glucopyranose units, respectively.
Cyclodextrins are known to increase the solubility of pharmaceuticals or drugs which are inherently insoluble or show a poor solubility in water. The employment of cyclodextrins and their derivatives helps to stabilize the drugs via the reversible formation of water soluble complexes. The formation of these complexes can prohibit or reduce the occurrence of side reactions that may take place between the drug and other species present in a solution. The drug molecule resides, either wholly or partly, within the central cavity of the cyclodextrin, or cyclodextrin derivative, to yield an inclusion complex. Consequently, various cyclodextrins and their derivatives have been deemed safe for use as pharmaceutical excipients, for example in Alfaxan® (WO 01/70234). Alfaxan® is an intravenous injectable anesthetic comprising complexes of alfaxalone and 2-hydroxy-β-cyclodextrin (commercially obtainable from Jurox Pty Ltd).
Typically β-cyclodextrin, and β-cyclodextrin derivatives, are utilized in the manufacture of medicaments. This is due to a number of reasons which includes the size of the lipophilic cavity, commercial availability, coupled with the low cost of the molecules, amongst other favorable attributes.
One important derivative is 2-hydroxypropyl-β-cyclodextrin which has been shown to be more water soluble and more toxicologically benign when compared to α-, β- and γ-cyclodextrin. Furthermore, in various studies, this derivative was shown to be tolerated in a range of animal species including rats, mice and dogs (S. Gould et al., Food and Chemical Technology, 43, 1451-1459, 2005).
When cyclodextrins and their derivatives are used to solubilize material in aqueous media, competition can occur between the various species present in the solution to occupy the central cavities of the cyclodextrin molecules. This means one compound may be solubilized to a greater degree in relation to any other compounds which may be present. This is an important point to consider when solubilizing pharmaceutical compounds with cyclodextrins, as ideally it is the active ingredient, e.g. a drug molecule, which is incorporated into the cyclodextrin and not any of the other excipients which may be present within a composition. For example, preservative species may be introduced into a liquid pharmaceutical composition in order to kill any bacteria, yeast or mold that may be accidently introduced into the composition. These preservative species may displace the drug molecule from the hydrophobic cavity of the cyclodextrin or cyclodextrin derivative, wherein the drug is unable to remain solubilized in the liquid medium and precipitates from the solution. The displacement of the drug molecule may lead to the formation of particulate matter, which has safety implications when the pharmaceutical composition is delivered via an injection.
The displacement of the drug means that the active pharmaceutical compound, for example a hydrophobic drug, is not fully solubilized. This then leads to a decreased efficacy, wherein the drug cannot perform its required function and induce the intended pharmacological and physiological response. In addition, in order for the preservative(s) to be effective against bacteria, yeast and mold, it/they should preferably remain unbound in the solution and not complexed in cyclodextrin hosts. If the preservative(s) form(s) complexes with the cyclodextrins in solution, the pharmaceutical composition may not meet preservation standards or adhere to prescribed regulations for medicaments.
Loftsson et al. (Drug Development and Industrial Pharmacy, 18 (13), 1477-1484, 1992), undertook a number of investigations which focused on 2-hydroxypropyl-β-cyclodextrin and its interactions with a selection of preservatives, including chlorobutanol, methylparaben, and propylparaben, which are commonly used in multi-dose pharmaceutical products. The interactions were shown to be twofold. Firstly, the chlorobutanol, methylparaben and propylparaben molecules were able to displace drug molecules from the cyclodextrin cavity which, in turn, hindered the effectiveness of the cyclodextrin in solubilizing the hydrophobic drug. Secondly, the antimicrobial activity of the preservatives chlorobutanol, methylparaben and propylparaben, were reduced or completely suppressed in the presence of the 2-hydroxypropyl-β-cyclodextrin due to the sequestration of the preservatives.
A number of patents have utilized cyclodextrins to increase the solubility of drugs in order to improve their delivery, albeit to a limited degree.
WO 01/70234 discloses a pharmaceutical composition comprising a water soluble cyclodextrin or a cyclodextrin derivative and Alfaxan®. The composition is stable and can be administered, in an anesthetically effective amount, to warm blooded animals, including birds and mammals, reptiles, fish and amphibians. Although the invention can be utilized as an effective anesthetic, the patent does not disclose, teach, nor suggest a composition comprising both a co-solvent and a preservative.
U.S. Pat. No. 6,358,935 and U.S. Pat. No. 6,723,353 disclose pharmaceutically acceptable compositions which include a liquid medium, a cyclodextrin component, chlorite present in an effective preserving amount and a pharmaceutically active component. The formulations do not include a co-solvent.
WO 2005/082416 discloses formulations which comprise β-cyclodextrin, a pharmaceutically acceptable preservative, wherein the preservatives are limited to meta-cresol, phenol or thimerosal, or combinations thereof, and a neurokinin receptor antagonist as the active pharmaceutical ingredient. The invention relies on the binding value of the active pharmaceutical ingredient with the β-cyclodextrins, to be greater than that of the preservative with the equivalent β-cyclodextrin molecule. An optimal balance between the cyclodextrin and anti-microbial preservative concentrations is required in order for the composition to adhere to the preservation standards and achieve acceptable injection-site-toleration. The patent does not disclose aqueous formulations which comprise at least one preservative and at least one co-solvent.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.